PROJECT SUMMARY Medicinal Chemistry and Chemical Biology Core The Medicinal Chemistry and Chemical Biology (MCCB) Core will be a key nexus point of the ADDD CENTER for the delivery on the primary objective of high quality lead molecules for prioritized disease targets that are suitable for further optimization into drug candidates. The MCCB Core strategy is to complement the deep Alzheimer?s Disease biology expertise and core technologies of the ADDD CENTER with CNS drug discovery and development experience and flexible medicinal chemistry approaches to expertly help select and prosecute a diverse portfolio of projects. The MCCB Core will work across all Technical Cores and the entire workflow of the ADDD CENTER to ensure a proficient integration of complimentary activities that move projects towards key milestones in a timely manner with optimal use of resources and shared learning/decision making. For all projects, the MCCB Core will establish hit discovery approaches that maximize the probability of finding novel chemical starting points, and then pursue multi-parameter hit optimization strategies that provide the best balance of pharmacology and drug-like properties that are reflected in ADDD CENTER approved lead molecules. The MCCB Core will be led by Dr. Alan Palkowitz, who will also be the co-PI for the ADDD CENTER. The composition of the MCCB Core will include dedicated medicinal chemists at Purdue University and flexible synthetic chemistry capacity contracted through AMRI. To ensure scientific diversity and ongoing expert input, a CNS Medicinal Chemistry Advisory Group will actively work within the MCCB Core and provide valuable advice to Dr. Palkowitz and team members on all scientific activities directed toward milestone contributions and deliverables. Additionally, the MCCB Core will integrate advanced in vivo testing (in partnership with the MODEL-AD Center) for later stage lead candidate optimization and selection in support of milestone decisions. The Specific AIMs of the MCCB Core are: 1. Provide input on target analysis and selection including assessment of druggability, design of validation experiments, and support of target enablement studies for applied drug discovery. 2. Work with all ADDD CENTER Technical Cores to design and implement the lead generation strategy for each prioritized target. 3. Analyze output form primary screening/molecular design efforts to identify potential hit series. Conduct iterative hit-to-lead optimizations studies to deliver go/no decisions on possible lead candidates that meet robust performance criteria.